CA1255682A - Azolylmethylcycloacetals, their preparation and their use as drugs - Google Patents
Azolylmethylcycloacetals, their preparation and their use as drugsInfo
- Publication number
- CA1255682A CA1255682A CA000472307A CA472307A CA1255682A CA 1255682 A CA1255682 A CA 1255682A CA 000472307 A CA000472307 A CA 000472307A CA 472307 A CA472307 A CA 472307A CA 1255682 A CA1255682 A CA 1255682A
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- Prior art keywords
- acids
- ylmethyl
- formula
- addition salts
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract of the Disclosure. Azolylmethylcycloacetals of the formula I
(I), where R is phenyl which can be substituted by halogen, or is C1-C6-alkyl, R1 is hydrogen or C1-C3-alkyl, Z
is CH or N, and m is 0 or 1, and their physiologically tolerated addition salts with acids and their preparation are described.
The novel substances have an antimycotic action.
(I), where R is phenyl which can be substituted by halogen, or is C1-C6-alkyl, R1 is hydrogen or C1-C3-alkyl, Z
is CH or N, and m is 0 or 1, and their physiologically tolerated addition salts with acids and their preparation are described.
The novel substances have an antimycotic action.
Description
~2~68~
- 1 - O.Z. 0050/36919 _Azolylmethylcycloacetals, their preparation and their use as drugs __ _ The present invention relates to novel azolyl-methylcycloacetals, processes for their preparation, thera-peutic agents which contain these compounds and can beused as antimycotics, and their use in the treatment of disorders.
4 large number of antimycotic active compounds, for example azolylmethylcarbinols, such as miconazole (German Laid~Open Application DOS 1,940,388), and azolyl-methyldioxolanes, such as ketoconazole (German Laid-Open ApQlication DOS Z,~04,096) have been disclosed, but their actions are not al~ays satisfactory (Zeitschrift fur Haut-krankheiten 56 (1981), 1109). The compounds of the pres-ent invention differ from the compounds of the last~men-tioned type essentially in the type of the substituents, especially in the 5- or 4-position of the dioxane or di-oxolane frame~ork, respectively.
We have found that azolylmethylcycloacetals of the formula I
~z~ Z ~O-C~z ~ R12-N3 where R is phenyl which can be substituted by halogen, or is c1-c6-alkyl~ R1 is hydrogen or C1-C3-alkyl, Z is CH or N and m is O or 1, and their physiologically tolerated addition salts with~acids possess good anti-microbial, in particular antimycotic, properties.
In formula I, R is preferably tert.-butyl, or is - phenyl which is substituted by halogen, in particular by chlorine. Among the latter compounds, 2~4-dichlorophenyl is particularly suitable.
R1 is preferably hydrogen or methyl.
The novel compounds of ~he formula I contain chiral centers and are obtained in general in the form of .~
~;~5~682
- 1 - O.Z. 0050/36919 _Azolylmethylcycloacetals, their preparation and their use as drugs __ _ The present invention relates to novel azolyl-methylcycloacetals, processes for their preparation, thera-peutic agents which contain these compounds and can beused as antimycotics, and their use in the treatment of disorders.
4 large number of antimycotic active compounds, for example azolylmethylcarbinols, such as miconazole (German Laid~Open Application DOS 1,940,388), and azolyl-methyldioxolanes, such as ketoconazole (German Laid-Open ApQlication DOS Z,~04,096) have been disclosed, but their actions are not al~ays satisfactory (Zeitschrift fur Haut-krankheiten 56 (1981), 1109). The compounds of the pres-ent invention differ from the compounds of the last~men-tioned type essentially in the type of the substituents, especially in the 5- or 4-position of the dioxane or di-oxolane frame~ork, respectively.
We have found that azolylmethylcycloacetals of the formula I
~z~ Z ~O-C~z ~ R12-N3 where R is phenyl which can be substituted by halogen, or is c1-c6-alkyl~ R1 is hydrogen or C1-C3-alkyl, Z is CH or N and m is O or 1, and their physiologically tolerated addition salts with~acids possess good anti-microbial, in particular antimycotic, properties.
In formula I, R is preferably tert.-butyl, or is - phenyl which is substituted by halogen, in particular by chlorine. Among the latter compounds, 2~4-dichlorophenyl is particularly suitable.
R1 is preferably hydrogen or methyl.
The novel compounds of ~he formula I contain chiral centers and are obtained in general in the form of .~
~;~5~682
- 2 o O.Z 0050/36919 racema~es or as diastereomer mixtures of erythro and threo forms. The ery~hro and threo diastereomers of the novel compounds can be separated, for example, by utili-zing their different solubiLities or by column chromato-graphy and can be isolated in pure form. Such pure dia-stereomer pairs can be converted to pure enantiomers by a conventional method. The pure diastereomers and enan-tiomers as ~ell as. mixtures of these can be used as anti-microbial agen~s.
Preferred acids for forming physiologically tole-rated sal~s are hydrohalic acids, such as hydrobromic acid and, in particular, hydrochloric acid, with which the novel compounds give particularly readily crystallizing salts~ Other examples are phosphoric acid, nitric acid, sulfuric a'cid, monofunctional and bifunctional carboxylic acids and hydroxycarboxylic acids, such as acetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid~ salicylic acid, sorbic acid or lactic acid, and.sulfonic acids, such as p-toluene-sulfonic acid and naphthalene-1,5-disulfonic acid.
The ncvel azolylmethylcyc'loacetals of the for-mula I can be prepared by a method in which a) a cycloacetal of the formula II
(CH2~
~ l~o C;l;~ CHZ-N3 where R, R1 and m have the above meanings and L is a leaving group which can undergo nucleophilic substitution, is reacted ~ith a compound of the formula III
N;~
~ yH (III), where Z has the above meanings, or b) a cycloacetal of the formula IV
~L2SS6~2
Preferred acids for forming physiologically tole-rated sal~s are hydrohalic acids, such as hydrobromic acid and, in particular, hydrochloric acid, with which the novel compounds give particularly readily crystallizing salts~ Other examples are phosphoric acid, nitric acid, sulfuric a'cid, monofunctional and bifunctional carboxylic acids and hydroxycarboxylic acids, such as acetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid~ salicylic acid, sorbic acid or lactic acid, and.sulfonic acids, such as p-toluene-sulfonic acid and naphthalene-1,5-disulfonic acid.
The ncvel azolylmethylcyc'loacetals of the for-mula I can be prepared by a method in which a) a cycloacetal of the formula II
(CH2~
~ l~o C;l;~ CHZ-N3 where R, R1 and m have the above meanings and L is a leaving group which can undergo nucleophilic substitution, is reacted ~ith a compound of the formula III
N;~
~ yH (III), where Z has the above meanings, or b) a cycloacetal of the formula IV
~L2SS6~2
- 3;- O.Z 0050/3691~
O--tCH ) R1 H0-CH ~ 2 ~ CH2~3 tIV), R
where R, R1 and m have the above meanings, ;s reacted ~ith a compound of the formula V
~ Y~ V~, where Z has the above meanings and Y ;5 a carbon or sulfur atom, or c) a compound of the formula VI
~ ~-C~z~O-R (~
where Z and R have the above meanings, is reacted with a compound of the formula VII
R1 ~CH2~ ~H
X m, ~YII),.
N~j-tlzC CHz411 where R1 and m have the above meanings, or d) a compound of the formula VIII
~J-C~t_<D tCHz~ VIII), z O-CHz CH2-~_ where Z, R, R1 and m have the above meanings and L is a leaving group which can undergo nucleophilic substitution, is reacted with an alkali metal azide, and the resulting compound is, if required, converted to its physiologically tolerated addition salts ~ith acids.
3L~25X~2 . . .
O--tCH ) R1 H0-CH ~ 2 ~ CH2~3 tIV), R
where R, R1 and m have the above meanings, ;s reacted ~ith a compound of the formula V
~ Y~ V~, where Z has the above meanings and Y ;5 a carbon or sulfur atom, or c) a compound of the formula VI
~ ~-C~z~O-R (~
where Z and R have the above meanings, is reacted with a compound of the formula VII
R1 ~CH2~ ~H
X m, ~YII),.
N~j-tlzC CHz411 where R1 and m have the above meanings, or d) a compound of the formula VIII
~J-C~t_<D tCHz~ VIII), z O-CHz CH2-~_ where Z, R, R1 and m have the above meanings and L is a leaving group which can undergo nucleophilic substitution, is reacted with an alkali metal azide, and the resulting compound is, if required, converted to its physiologically tolerated addition salts ~ith acids.
3L~25X~2 . . .
- 4 - O.Z. OOS0/36919 Among these processes, the last-mentioned one ~d) is preferred.
Reaction a) is preferably carried out in the pres-ence of a solvent or d;luent, with or without the addition of an inorganic or organic base and of a reaction accele-rator, at from 10 to 120C. The preferred solvents and diluents include ketones, such as acetone, methyl ethyl ketone or cyrlohexanone, nitriles such as acetonitrile, esters~ such as ethyl acetate, ethers, such as diethyl ether, tetrahydrofuran or dioxane, sulfoxides, such as dimethyl sulfoxide, amides, such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone, and sulfolane, Or mixtures of these.
Suitable bases, which, if necessary, can also be used in the reaction as acid acceptors, are alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, pyridine, 4-dimethylaminopyri-dine and excess 1~2,4-triazole or imidazole. However, other conventional bases can also be used.
Preferred reaction accelerators are metal halides, such as sodium iodide or potassium iodide, quaternary ammonium salts, such as tetrabutylammonium chloride, bromide or iodide or benzyltriethylammonium chloride or bromide, and crown ethers, such as 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6 or dicyclohexano-18-crown-o.
The reaction is carried out in general at from 1û
to 120C, under atmospheric or superatmospheric pres-sure, continuously or batchwise.
Reaction a) can also be carried out as follows:compound III is converted to a metal salt, preferably an alkali metal salt, and this is reacted with compound II at from -10 to +120C, in the presence or absence of a solvent or diluent and with or without the addition - of a strong inorganic or organic base. The preferred sol-vents and diluents include amides, such as dimethylform-~S568~
- S - O.Z. 0050/3691~
amide, diethylformamide, dimethylacetamide~ diethylacet-amide, N-methylpyrrolidone, hexamethylphosphorotriamide and sulfoxides, such as dimethyl sulfoxide and sulfolane.
Examples of suitable bases, which can also be used in the reaction as acid acceptors, are alkali metal hyd-rides, such as lithium hydride, sodium hydride or potas-s;um hydride, alkali metal amides, such as sodium amide or potassium amide, and sodium tert.-butoxide, potassium tert.-butoxide, lithium triphenylmethyl, sodium-triphenyl-methyl, potassium-triphenylmethyl, naphthalene-lithium, p sodium and naphthalene-potassium.
L is preferably a halogen atom or a reactive ester group, eg. the mesyla.e group.
Reaction b) is carried out in a solvent or diluent~
suitable solvents and diluents being polar organic sol-vents, such as nitriles, eg. acetonitrile, sulfoxides, eg. dimethyl sulfoxide, formamides, eg. dimethylformamide, ketones, eg. acetone, ethers, eg. diethyl ether or tetra-hydrofuran, and in particular chlorohydrocarbons, eg. methy-Z0 lene.chlorlde or chloroform~
The reaction is carried out in general at from û
to 100C, preferably at from 20 to 80C. When a sol-vent is present, the procedure is advantageously effected at the boiling point of the particular solvent.
Z5 In carrying out process b), about 1 mole of bis-1,2,4-triazol-1-yl ketone or bis-imidazol-1-yl ketone, or preferably about 1 mole of bis-1,2,4-triazol-1-yl sulf-oxide or b;s-im;dazol-1-yl sulfoxide, is employed per mole-of the compound of the formula IV, or bis-1,2,4-triazol-1-yl sulfoxide or bis-imidazol-1-yl sulfoxide is produced in situ.
Reaction c) is preferably carried out by refluxing the two reactants in a suitable organic solvent, prefer-ably in the presence of a simple alcohol, such as ethanol, propanol, butanol or pentanol, and in the presence of a suitable strong acid, such as 4-methylbenzenesulfonic acid, with azeotropic removal of water. Examples of suitable ~ 25S Ei~
" - 6 - O.Z~ 0050/36919 organic solvents are aromatic hydrocarbons, such as benzene, methylbenzene or dimethylbenzene, saturated hydrocarbons, such as cyclohexane, and mixtures of these.
Reaction d) is preferably carried out in the presence of a solvent or diluent, with or without the ad-dition of an inorgan;c or organic base and of a reaction accelerator, at from 10 to 1Z0C. The preferred so'vents and diluen~s include ketones, such as acetone, methyl ethyl ketone or cyclohexanone, nitriles, such as aceto-nitrile, esters, such as ethyl acetate, ethers, such asdie~hyl ether, tetrahydrofuran or dioxane, sulfoxides, such as dimethyl sulfoxide, amides~ such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone, and sulfolane and mixtures of these.
~5Examples of suitable bases, which can, if neces-sary, also be used in the reaction as acid acceptors, are alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkal; metal carbonates, such as sodium carbonate, potassium carbonate, sodium bi-carbonate or potassium b;carbonate, pyridine, 4-dimethyl-aminopyridine and an excess of alkali metal azide.
Suitable reaction accelerators are the substances stated for process a).
The reaction is carried out in general at from 10 to 1Z0C, under atmospheric or superatmospheric pres-sure, continuously or batchwise.
The resulting compounds of the formula I are iso-lated by a conventional method and, if required, are con-verted to their salts with the stated acids.
30The starting compounds II are obtainable by the following route:
VII ~ L-C~2-~0~ H > II
~%) For this purpose, the reactants are reacted by pro-cess b) described above, with azeotropic removal of water.
1:25~8~
- 7 - .Z. 0050/36919 The starting compounds of the formula VI are known; those which are unkno~n can be prepared in a conven-tional manner, for example as described in 5erman Patent 2~549,798 or German Laid-Open Application DOS 2,940,133.
S The startir,g compounds VII are obtainable in accor-dance with the following equa~ion:
R1 (C~12~m~H_~ X'lZ)m~a)~similarly tQ R >~H2 OH2C CH2~H H t HOH2C CH2~ proc~ss dN;H2C c~
(X) (XI~ (XI~
Some of the s~arting compounds of the formula VIII
are known ~rom the literature (J. Med~ ChemO 1Z (1969), 788 and 22 (1979) 100~, and U.S~ Patents 4,1û1,o64~
4,101,665~ 4,13~,540 and 4,338,3Z7); ~hose which are un-known can be prepared in a similar mannerO
Surprisingly~ the novel azole derivatives, in ad-dition to possessing very good in vitro antimycotic acti-vity, also have a better therapeutically useful in vivo activity than conven~ional preparations, in particular against dermatophytes, but also against Candida. They also possess antibacterial activityO The active compounds according to the invention tierefore constitute a valu-able enrichment o~ the art~
The action against dermatophytes, bacteria andprotozoa can be demonstrated by methods as described in~
for example, P. Klein, ~akteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlag aerlin, 1957. The action against yeasts was demonstrated in the pseudomycelium and mycelium phase tests with Can-dida albicans (cfo German Laid~Open Application DOS 3~10~093)o The minimum inhibitory concentrations (MIC) achi-eved in the agar d;lution test were determined~
The results are summarized in Table 1 ~,~2S~
~ 8 - O.Z. 0050/36919 In ~itro antim~ of the novel c_mpounds Substance Epid. ~icrosp. Trichoph. Cand..Cand. Abs. Asp. Mucor ^,taph.
of Example flocc. ferrug. ment. alb. alb. corym. fum. pus aur.
No. yeast mycelium phase onase 1 O.ZS 0.125 1 >16 0.0625 >16 4 8 128 2 0.0156 0.0156 0.0312 >16 0.0625 4 1 1 128 7 On1Z5 0.0625 0.0125 >16 0.0625 16 0.5 8 128 Keto~ 4 1 2 >128 O.G312 32128 16 128 conazole In the guinea pig trichophytosis model (Tricho-phyton mentagrophytes; cf. Heffter-Heubner: Handbuch der exp~ Pharmakologie~ Vol. XVI/II A), the novel compounds, when apPlied externally, show no recurrences and are more effective than the comparison substance also tested.
The action of the test substances when used topically in the experimental Candida albicans vaginitis model was also good~
The novel compounds are also orally effective.
In the model of experimental generalized candidosis of the mouse or the model of experimental Candida alb;cans vaginitis in the rat, complete elimination of the infec-tions could be achieved when the test substances ~ere ad-ministered orally in small therapeutic doses.
The novel compounds are therefore particularly useful for the treatment of fungal infections in man and animals by external application or oral administration.
~xamples of fields of ind;cation in man and animals are dermatomycoses, in particular~those caused by dermato-phytes, such as species of the genera Epidermatophyton, Microsporum or Trichophyton, yeasts, such as species of the genera Candida, and molds, such as species of the genera AsPerg;llus, Mucor and Absidia~
The compounds can be used alone or together ~ith other conventional active compounds, in particular anti~
biotics.
The chemotherapeutic agents or formulations are ~ ;5~
- 9 - 0.Z. 0050/3~919 prepared in a conventional manner, in particular by mix-ing an appropriate dose with conventional solid, semi-solid or liquid carriers or diluents and the conventional pharmaceutical auxiliaries, in accordance with the desired route of administration (cf. H~. Sucker et al., Pharma-zeutische Technologie, Thieme-Verlag, Stuttgart, 1978.) Examples of suitable formulations are tablets, coated tablets, capsules, pills, aqueous solutions, sus-pensions and emuLsionsO and if appropriate sterile injac-table solutions, non aqueous emulsions, suspensions andsolutions, ointments, creams~ pastes, lotions, etc.
The therapeu~ically active compound is preferably present in the pharmaceutical formulations in a concentra-tion of from 0.01 to 90~ by ~eight, based on the total mixture.
~ o achieve the desired results in the case of oral administration either in human or in veterinary medi~
cine, the active compound or compounds can be administered in general in amounts of from about 1.0 to about 50~0, preferably from 2 to 10, mg/kg of body weight per day, preferably in the form of several single doses. However, it may be necessary to deviate from the stated doses, and to do this as a function of the nature and severity of the disorder, the type of formulation and the route of adminis-tration of the drug, as well as the period of or interval between administrations. Thus, it may be sufficient in some cases to use less than the abovementioned amount of active compounds, ~hile in other cases the above amount of active compound has to be exceeded.
The Examples and methods which follow illustrate the preparation of the novel compounds and their inter~
mediates.
a) Preparation of the intermediates A solution of 10.4 9 of triazole in 20 ml of dry dimethylformamide was added to 2.2 9 of sodium hydride t50% strength dispersion in mineral oil~ in 10 ml of dry ~2556~3~
- 10 - O.Z. 0050/36919 dimethylformamide at 5C, and the mixture was stirred for 10 minutes at room temperature. 22.3 9 of cis-2-bromo-methyl-2-(2,4-dichlorophenyl)-4-benzoyloxymethyl-1,3-di-oxolane in 100 ml of dry dimethylformamide were then added, 1 9 of Potassium iodide was introduced and the mixture was then stirred overnight at 145C~ The cooled reaction solution was poured into water and axtracted with ethyl acetate. The extracts were evaporated down, ~he residue was taken up ;n diethyl ether, the basic components were preciDitated w;th hydrogen chloride gas, and the super natant solvent was decanted. The remaining ~recipi~ate was taken up in tO0 mL of dioxane, 100 ml of ZN sodium hydroxide solution were added, and the stirred mixture was refluxed for 2 hours. The reaction solution was ~va-porated down to half its volume in a rotary evaporator,the residue ~as poured into water and the mixture was extracted with methylene chloride. The extracts were washed neutral~ dried over magnesium sulfate and filtered~
The solvent was evaporated o~f and the residue was recrys-tallized from ethyl acetate to give 13~7 9 t83%) of cis-2-(1,2,4-triazol-1-ylmethyl)-2-t2,4-d;chlorophenyl)-4-hydroxymethyl-1,3-dioxolane of melting point 134-137C.
1~63 9 of methanesulfonyl chloride were added dropwise to 3~96 9 of cis-2-~1,2,4-triazol-1-ylmethyl)-2-~2,4-dichlorophenyl)-4-hydroxymethyl-1,3-dioxolane in 50 m~
of dry methylene chlor;de and 1.44 9 of triethylamine, and the reaction solution was stirred at room temperature.
When the reaction was complete, the mixture was poured onto water and extracted with~methylene chloride, the organic phase was washed with water, dried over magnesium sulfate and filtered~ and the solvent was evaporated off.
The residue was crystallized from isoproPanol and gave 4.2 9 t85.7X) of cis-Z-t1,2,4-triazol-1-ylmethyl)-2-(2,4-dichloroDhenyl)-4-methanesulfonyloxymethyl-1,3-dioxolane of melting point 95A5-970C.
b) Prepara~ion of the end product 4.2 g of cis-2-t1,2,4-triazol-1-ylmethyl)-2-t2,4-~255682 ~ O~Z. 0050/36919dichlorophenyl)-4-methanesulfonyloxymethyl-1,3-dioxolane were stirred with 6.6 9 of sodium azide in 50 ml of dry dimethylformamide for 30 minutes at 100C. The reaction solution was poured onto water and extracted with ethyl S acetate, the extracts were washed with water, dried over magnesium sulfate and evaporated down, and the sirupy residue ~as taken up in acetone~ When hydrogen chloride was introduced into the solution, 3.5 g t86~7X) of cis-2-(1,2,4Otriazol-1-yLme~hyl)~2-~2,4-dichlorophenyl)-4-azidomethyl-1,3-dioxolane were obtained in the form of the hydrochloride of me~ting po;nt 164-166C.
EXAMPLE Z
a) Pre~aration of the intermediates Z68 9 oP -bromo-2,4-dichloroacetophenone, 121 9 of 2-hydroxymethyl-2-methylpropane-1,3~diol and 2 9 of p-toluenesulfonic acid in 1000 ml of toLuene were refluxed under a water separator. When the reaction was comp~ete, the cold solution was washed neutral with sodium carbon-a~e solution and water and dried over sodium suLfate, the solvent was evaporated off, and the oily residue was puri-fied over an 80n 9 silica gel column, using a Z0:1 hexane/
ethyl acetate mixture~ When the solvent had been evapo-rated off, the combined product fractions gave Z55 9 ~69Z) of Z-bromomethyl-Z-(2,4-dichlorophenyl)-5-hydroxymethyl-
Reaction a) is preferably carried out in the pres-ence of a solvent or d;luent, with or without the addition of an inorganic or organic base and of a reaction accele-rator, at from 10 to 120C. The preferred solvents and diluents include ketones, such as acetone, methyl ethyl ketone or cyrlohexanone, nitriles such as acetonitrile, esters~ such as ethyl acetate, ethers, such as diethyl ether, tetrahydrofuran or dioxane, sulfoxides, such as dimethyl sulfoxide, amides, such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone, and sulfolane, Or mixtures of these.
Suitable bases, which, if necessary, can also be used in the reaction as acid acceptors, are alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, pyridine, 4-dimethylaminopyri-dine and excess 1~2,4-triazole or imidazole. However, other conventional bases can also be used.
Preferred reaction accelerators are metal halides, such as sodium iodide or potassium iodide, quaternary ammonium salts, such as tetrabutylammonium chloride, bromide or iodide or benzyltriethylammonium chloride or bromide, and crown ethers, such as 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6 or dicyclohexano-18-crown-o.
The reaction is carried out in general at from 1û
to 120C, under atmospheric or superatmospheric pres-sure, continuously or batchwise.
Reaction a) can also be carried out as follows:compound III is converted to a metal salt, preferably an alkali metal salt, and this is reacted with compound II at from -10 to +120C, in the presence or absence of a solvent or diluent and with or without the addition - of a strong inorganic or organic base. The preferred sol-vents and diluents include amides, such as dimethylform-~S568~
- S - O.Z. 0050/3691~
amide, diethylformamide, dimethylacetamide~ diethylacet-amide, N-methylpyrrolidone, hexamethylphosphorotriamide and sulfoxides, such as dimethyl sulfoxide and sulfolane.
Examples of suitable bases, which can also be used in the reaction as acid acceptors, are alkali metal hyd-rides, such as lithium hydride, sodium hydride or potas-s;um hydride, alkali metal amides, such as sodium amide or potassium amide, and sodium tert.-butoxide, potassium tert.-butoxide, lithium triphenylmethyl, sodium-triphenyl-methyl, potassium-triphenylmethyl, naphthalene-lithium, p sodium and naphthalene-potassium.
L is preferably a halogen atom or a reactive ester group, eg. the mesyla.e group.
Reaction b) is carried out in a solvent or diluent~
suitable solvents and diluents being polar organic sol-vents, such as nitriles, eg. acetonitrile, sulfoxides, eg. dimethyl sulfoxide, formamides, eg. dimethylformamide, ketones, eg. acetone, ethers, eg. diethyl ether or tetra-hydrofuran, and in particular chlorohydrocarbons, eg. methy-Z0 lene.chlorlde or chloroform~
The reaction is carried out in general at from û
to 100C, preferably at from 20 to 80C. When a sol-vent is present, the procedure is advantageously effected at the boiling point of the particular solvent.
Z5 In carrying out process b), about 1 mole of bis-1,2,4-triazol-1-yl ketone or bis-imidazol-1-yl ketone, or preferably about 1 mole of bis-1,2,4-triazol-1-yl sulf-oxide or b;s-im;dazol-1-yl sulfoxide, is employed per mole-of the compound of the formula IV, or bis-1,2,4-triazol-1-yl sulfoxide or bis-imidazol-1-yl sulfoxide is produced in situ.
Reaction c) is preferably carried out by refluxing the two reactants in a suitable organic solvent, prefer-ably in the presence of a simple alcohol, such as ethanol, propanol, butanol or pentanol, and in the presence of a suitable strong acid, such as 4-methylbenzenesulfonic acid, with azeotropic removal of water. Examples of suitable ~ 25S Ei~
" - 6 - O.Z~ 0050/36919 organic solvents are aromatic hydrocarbons, such as benzene, methylbenzene or dimethylbenzene, saturated hydrocarbons, such as cyclohexane, and mixtures of these.
Reaction d) is preferably carried out in the presence of a solvent or diluent, with or without the ad-dition of an inorgan;c or organic base and of a reaction accelerator, at from 10 to 1Z0C. The preferred so'vents and diluen~s include ketones, such as acetone, methyl ethyl ketone or cyclohexanone, nitriles, such as aceto-nitrile, esters, such as ethyl acetate, ethers, such asdie~hyl ether, tetrahydrofuran or dioxane, sulfoxides, such as dimethyl sulfoxide, amides~ such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone, and sulfolane and mixtures of these.
~5Examples of suitable bases, which can, if neces-sary, also be used in the reaction as acid acceptors, are alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkal; metal carbonates, such as sodium carbonate, potassium carbonate, sodium bi-carbonate or potassium b;carbonate, pyridine, 4-dimethyl-aminopyridine and an excess of alkali metal azide.
Suitable reaction accelerators are the substances stated for process a).
The reaction is carried out in general at from 10 to 1Z0C, under atmospheric or superatmospheric pres-sure, continuously or batchwise.
The resulting compounds of the formula I are iso-lated by a conventional method and, if required, are con-verted to their salts with the stated acids.
30The starting compounds II are obtainable by the following route:
VII ~ L-C~2-~0~ H > II
~%) For this purpose, the reactants are reacted by pro-cess b) described above, with azeotropic removal of water.
1:25~8~
- 7 - .Z. 0050/36919 The starting compounds of the formula VI are known; those which are unkno~n can be prepared in a conven-tional manner, for example as described in 5erman Patent 2~549,798 or German Laid-Open Application DOS 2,940,133.
S The startir,g compounds VII are obtainable in accor-dance with the following equa~ion:
R1 (C~12~m~H_~ X'lZ)m~a)~similarly tQ R >~H2 OH2C CH2~H H t HOH2C CH2~ proc~ss dN;H2C c~
(X) (XI~ (XI~
Some of the s~arting compounds of the formula VIII
are known ~rom the literature (J. Med~ ChemO 1Z (1969), 788 and 22 (1979) 100~, and U.S~ Patents 4,1û1,o64~
4,101,665~ 4,13~,540 and 4,338,3Z7); ~hose which are un-known can be prepared in a similar mannerO
Surprisingly~ the novel azole derivatives, in ad-dition to possessing very good in vitro antimycotic acti-vity, also have a better therapeutically useful in vivo activity than conven~ional preparations, in particular against dermatophytes, but also against Candida. They also possess antibacterial activityO The active compounds according to the invention tierefore constitute a valu-able enrichment o~ the art~
The action against dermatophytes, bacteria andprotozoa can be demonstrated by methods as described in~
for example, P. Klein, ~akteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlag aerlin, 1957. The action against yeasts was demonstrated in the pseudomycelium and mycelium phase tests with Can-dida albicans (cfo German Laid~Open Application DOS 3~10~093)o The minimum inhibitory concentrations (MIC) achi-eved in the agar d;lution test were determined~
The results are summarized in Table 1 ~,~2S~
~ 8 - O.Z. 0050/36919 In ~itro antim~ of the novel c_mpounds Substance Epid. ~icrosp. Trichoph. Cand..Cand. Abs. Asp. Mucor ^,taph.
of Example flocc. ferrug. ment. alb. alb. corym. fum. pus aur.
No. yeast mycelium phase onase 1 O.ZS 0.125 1 >16 0.0625 >16 4 8 128 2 0.0156 0.0156 0.0312 >16 0.0625 4 1 1 128 7 On1Z5 0.0625 0.0125 >16 0.0625 16 0.5 8 128 Keto~ 4 1 2 >128 O.G312 32128 16 128 conazole In the guinea pig trichophytosis model (Tricho-phyton mentagrophytes; cf. Heffter-Heubner: Handbuch der exp~ Pharmakologie~ Vol. XVI/II A), the novel compounds, when apPlied externally, show no recurrences and are more effective than the comparison substance also tested.
The action of the test substances when used topically in the experimental Candida albicans vaginitis model was also good~
The novel compounds are also orally effective.
In the model of experimental generalized candidosis of the mouse or the model of experimental Candida alb;cans vaginitis in the rat, complete elimination of the infec-tions could be achieved when the test substances ~ere ad-ministered orally in small therapeutic doses.
The novel compounds are therefore particularly useful for the treatment of fungal infections in man and animals by external application or oral administration.
~xamples of fields of ind;cation in man and animals are dermatomycoses, in particular~those caused by dermato-phytes, such as species of the genera Epidermatophyton, Microsporum or Trichophyton, yeasts, such as species of the genera Candida, and molds, such as species of the genera AsPerg;llus, Mucor and Absidia~
The compounds can be used alone or together ~ith other conventional active compounds, in particular anti~
biotics.
The chemotherapeutic agents or formulations are ~ ;5~
- 9 - 0.Z. 0050/3~919 prepared in a conventional manner, in particular by mix-ing an appropriate dose with conventional solid, semi-solid or liquid carriers or diluents and the conventional pharmaceutical auxiliaries, in accordance with the desired route of administration (cf. H~. Sucker et al., Pharma-zeutische Technologie, Thieme-Verlag, Stuttgart, 1978.) Examples of suitable formulations are tablets, coated tablets, capsules, pills, aqueous solutions, sus-pensions and emuLsionsO and if appropriate sterile injac-table solutions, non aqueous emulsions, suspensions andsolutions, ointments, creams~ pastes, lotions, etc.
The therapeu~ically active compound is preferably present in the pharmaceutical formulations in a concentra-tion of from 0.01 to 90~ by ~eight, based on the total mixture.
~ o achieve the desired results in the case of oral administration either in human or in veterinary medi~
cine, the active compound or compounds can be administered in general in amounts of from about 1.0 to about 50~0, preferably from 2 to 10, mg/kg of body weight per day, preferably in the form of several single doses. However, it may be necessary to deviate from the stated doses, and to do this as a function of the nature and severity of the disorder, the type of formulation and the route of adminis-tration of the drug, as well as the period of or interval between administrations. Thus, it may be sufficient in some cases to use less than the abovementioned amount of active compounds, ~hile in other cases the above amount of active compound has to be exceeded.
The Examples and methods which follow illustrate the preparation of the novel compounds and their inter~
mediates.
a) Preparation of the intermediates A solution of 10.4 9 of triazole in 20 ml of dry dimethylformamide was added to 2.2 9 of sodium hydride t50% strength dispersion in mineral oil~ in 10 ml of dry ~2556~3~
- 10 - O.Z. 0050/36919 dimethylformamide at 5C, and the mixture was stirred for 10 minutes at room temperature. 22.3 9 of cis-2-bromo-methyl-2-(2,4-dichlorophenyl)-4-benzoyloxymethyl-1,3-di-oxolane in 100 ml of dry dimethylformamide were then added, 1 9 of Potassium iodide was introduced and the mixture was then stirred overnight at 145C~ The cooled reaction solution was poured into water and axtracted with ethyl acetate. The extracts were evaporated down, ~he residue was taken up ;n diethyl ether, the basic components were preciDitated w;th hydrogen chloride gas, and the super natant solvent was decanted. The remaining ~recipi~ate was taken up in tO0 mL of dioxane, 100 ml of ZN sodium hydroxide solution were added, and the stirred mixture was refluxed for 2 hours. The reaction solution was ~va-porated down to half its volume in a rotary evaporator,the residue ~as poured into water and the mixture was extracted with methylene chloride. The extracts were washed neutral~ dried over magnesium sulfate and filtered~
The solvent was evaporated o~f and the residue was recrys-tallized from ethyl acetate to give 13~7 9 t83%) of cis-2-(1,2,4-triazol-1-ylmethyl)-2-t2,4-d;chlorophenyl)-4-hydroxymethyl-1,3-dioxolane of melting point 134-137C.
1~63 9 of methanesulfonyl chloride were added dropwise to 3~96 9 of cis-2-~1,2,4-triazol-1-ylmethyl)-2-~2,4-dichlorophenyl)-4-hydroxymethyl-1,3-dioxolane in 50 m~
of dry methylene chlor;de and 1.44 9 of triethylamine, and the reaction solution was stirred at room temperature.
When the reaction was complete, the mixture was poured onto water and extracted with~methylene chloride, the organic phase was washed with water, dried over magnesium sulfate and filtered~ and the solvent was evaporated off.
The residue was crystallized from isoproPanol and gave 4.2 9 t85.7X) of cis-Z-t1,2,4-triazol-1-ylmethyl)-2-(2,4-dichloroDhenyl)-4-methanesulfonyloxymethyl-1,3-dioxolane of melting point 95A5-970C.
b) Prepara~ion of the end product 4.2 g of cis-2-t1,2,4-triazol-1-ylmethyl)-2-t2,4-~255682 ~ O~Z. 0050/36919dichlorophenyl)-4-methanesulfonyloxymethyl-1,3-dioxolane were stirred with 6.6 9 of sodium azide in 50 ml of dry dimethylformamide for 30 minutes at 100C. The reaction solution was poured onto water and extracted with ethyl S acetate, the extracts were washed with water, dried over magnesium sulfate and evaporated down, and the sirupy residue ~as taken up in acetone~ When hydrogen chloride was introduced into the solution, 3.5 g t86~7X) of cis-2-(1,2,4Otriazol-1-yLme~hyl)~2-~2,4-dichlorophenyl)-4-azidomethyl-1,3-dioxolane were obtained in the form of the hydrochloride of me~ting po;nt 164-166C.
EXAMPLE Z
a) Pre~aration of the intermediates Z68 9 oP -bromo-2,4-dichloroacetophenone, 121 9 of 2-hydroxymethyl-2-methylpropane-1,3~diol and 2 9 of p-toluenesulfonic acid in 1000 ml of toLuene were refluxed under a water separator. When the reaction was comp~ete, the cold solution was washed neutral with sodium carbon-a~e solution and water and dried over sodium suLfate, the solvent was evaporated off, and the oily residue was puri-fied over an 80n 9 silica gel column, using a Z0:1 hexane/
ethyl acetate mixture~ When the solvent had been evapo-rated off, the combined product fractions gave Z55 9 ~69Z) of Z-bromomethyl-Z-(2,4-dichlorophenyl)-5-hydroxymethyl-
5-methyl-1,3-dioxane as a viscous oily m;xture of the two diastereomers~ The mixture gradually solidified (melting range: 90-100C)~
21.3 9 of benzoyl chloride were added to 45.8 9 of this diastereomer mixture,~and the resulting mixture was then stirred with 15~3 9 of triethylamine in 2D0 ml of dry tetrahydrofuran for Z hours at room temperature.
The precipitate was filtered off, the solvent was substan-tially evaporated off, the residue was taken up in ethyl acetate, and the solution was washed with ~ater, dried over sodium sulfate, filtered and evaporated do~n. The residue was recrystallized from ethanol to give 37 9 (63~4%~ of 2-bromomethyl-2-(2,4-dichlorophenyl)-5-benzoyl-Si68~
~ 12 ~ O.Z. OOS0/36919oxymethyl-S-methyL-1,3-dioxane (isomer A) of melting poin~
139-142C.
8.5 g of this product (isomer A) and 4.9 9 of imidazole were refluxed with 0~3 9 of potassium iodide in 30 ml of dry dimethylformamide under nitrogen.
When the reaction was complete, the cold solution was poured on~o water and extracted with ethyl acetate, the extracts were evaporated down, the residue ~as taken up in 50 ml of dioxane, and the s~irred solution was re-fluxed with 1û ml of 2N sodium hydroxide solution for 1.5hours. The co(d solution was poured onto water and ex-tracted with methylene chloride, the extracts were dried over sodiun sulfate, the solvent was evaporated off and the resulting residue was recrystallized from diethyl ether to g;ve 4.7 9 ~73.5%) of 2-timidazol-1-ylmethyl)-2-(2,4-d;chlorophenyl)-5-hydroxymethyl-5-methyl-1,3-d;oxane tisomer A) of melting point 174-175C.
b) Preparation of the end product 1.1 9 of p-toluenesulfonyl chloride were added to 2û 1~78 9 of this product tisomer A) and 0.6 9 of triethyl-amlne in 30 ml of dry methylene chloride. After 2 hours' stirring at room temperature, the mixture was poured onto water and extracted with methylene chloride~ and the organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated down.
The res;due was taken up in 20 ml of dry dimethylfor-mamide, 3.3 9 of sod;um azide were added and the mixture was stirred for 2 hours at 100C. The cold solution ~as poured onto water and extracted with ethyl acetate, and the organic phase was washed with water, dried over sodium sul-fate, filtered and evaporated to dryness. The residue was recrystallized from diisopropyl ether to give 1.3 ~9 (68%) of 2-(imidazol-1-ylmethyl)-2-t2,4-dichloro-phenyl)~S-azido-methyl-5-methyl-1,3-dioxane of melting point 132 to 133C.
The compounds listed in Table 2 were prepared, or can be prepared, by methods similar to those described in Examples 1 and 2.
~2~56~
- - 13 - O.Z. 0050/3691 TAB~E 2 Example z a Rl m Salt Mp.'-C
3 N C(CH3)3 C~3 z ,4~Cl~6~3 C2~; 1 ~ C(CE13)3 H O '~J.Cl 1 ,Z 173
21.3 9 of benzoyl chloride were added to 45.8 9 of this diastereomer mixture,~and the resulting mixture was then stirred with 15~3 9 of triethylamine in 2D0 ml of dry tetrahydrofuran for Z hours at room temperature.
The precipitate was filtered off, the solvent was substan-tially evaporated off, the residue was taken up in ethyl acetate, and the solution was washed with ~ater, dried over sodium sulfate, filtered and evaporated do~n. The residue was recrystallized from ethanol to give 37 9 (63~4%~ of 2-bromomethyl-2-(2,4-dichlorophenyl)-5-benzoyl-Si68~
~ 12 ~ O.Z. OOS0/36919oxymethyl-S-methyL-1,3-dioxane (isomer A) of melting poin~
139-142C.
8.5 g of this product (isomer A) and 4.9 9 of imidazole were refluxed with 0~3 9 of potassium iodide in 30 ml of dry dimethylformamide under nitrogen.
When the reaction was complete, the cold solution was poured on~o water and extracted with ethyl acetate, the extracts were evaporated down, the residue ~as taken up in 50 ml of dioxane, and the s~irred solution was re-fluxed with 1û ml of 2N sodium hydroxide solution for 1.5hours. The co(d solution was poured onto water and ex-tracted with methylene chloride, the extracts were dried over sodiun sulfate, the solvent was evaporated off and the resulting residue was recrystallized from diethyl ether to g;ve 4.7 9 ~73.5%) of 2-timidazol-1-ylmethyl)-2-(2,4-d;chlorophenyl)-5-hydroxymethyl-5-methyl-1,3-d;oxane tisomer A) of melting point 174-175C.
b) Preparation of the end product 1.1 9 of p-toluenesulfonyl chloride were added to 2û 1~78 9 of this product tisomer A) and 0.6 9 of triethyl-amlne in 30 ml of dry methylene chloride. After 2 hours' stirring at room temperature, the mixture was poured onto water and extracted with methylene chloride~ and the organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated down.
The res;due was taken up in 20 ml of dry dimethylfor-mamide, 3.3 9 of sod;um azide were added and the mixture was stirred for 2 hours at 100C. The cold solution ~as poured onto water and extracted with ethyl acetate, and the organic phase was washed with water, dried over sodium sul-fate, filtered and evaporated to dryness. The residue was recrystallized from diisopropyl ether to give 1.3 ~9 (68%) of 2-(imidazol-1-ylmethyl)-2-t2,4-dichloro-phenyl)~S-azido-methyl-5-methyl-1,3-dioxane of melting point 132 to 133C.
The compounds listed in Table 2 were prepared, or can be prepared, by methods similar to those described in Examples 1 and 2.
~2~56~
- - 13 - O.Z. 0050/3691 TAB~E 2 Example z a Rl m Salt Mp.'-C
3 N C(CH3)3 C~3 z ,4~Cl~6~3 C2~; 1 ~ C(CE13)3 H O '~J.Cl 1 ,Z 173
6 N 294~C12-C6H3 n C3~, ' ca 2~4-C12-C6H3 E~ 85 8 C'd 2, 4-C12~ 6~3 Cd( Ca3 ) 2 9 CX C( CH3 ) 3 c~3 CX 5(C'd3)3 H
11 Cd C( C'd ) H O
12 ~ 4-Cl-C6H4 13 ~ 2 ~4-C12-C6H3 C2 5 14 N 4_F-C6d4 H O
l S CH 4 F C 6 4 Examples of pharmaceutical formulations:
EXAMP~E A
Tablet containing 250 mg of active compound composition for 1~000 tablets~
Active compound of Example No. 7 250 9 Potato starch 100 9 Lactose 50 9 4X strength gelatine solution 45 9 Talc 10 9 ~2~5~
- 14 - O.Z. 0050!36919 Preparation:
The finely powdered active compound, po~ato starch and lactose are mixed. The mixture is moistened thor-oughly with about 4~ 9 of 4~ strenyth gelatine solution and then converted to fine granules, and these a~e dried.
The dry granules are passed through a sieve and mixed with -10 g of talG and the mixture is converted to tablets on a rotary tablet machine. The tablets are introduced into tightly closing polypropylene containers.
Cream containing 1% of active compound Active compound of Example NoO 71.0 9 Glycerol monostearate 10~0 9 Cetyl alcohol 4~0 g 15 Polyethylene glycol-400 stearate10.0 9 Polyethylene glycol sorbitan monostearate 10.0 9 Propylene glycol 6.0 9 Methyl p-hydroxybenzoate 0.2 g Deminerali~ed water to ma~e up tolOO.û g Pre~ation:
The very finely powdered active compound is sus-pended in propylene glycol, and the suspension is stirred ;nto a melt cons;st;ng of glycerol monostearate, cetyl alcohol, polyethylene glycol-4ûO stearate and polyethy-ZS lene glycol sorb;tan monostearate, the melt being heatedat 65C. An aqueous solution of the methyl p-hydroxy-benzoate, at 70C, ;s emulsif;ed with this mixture.
When it has cooled, the cream is homogenized by means of a colloid mill and is introduced into tubes.
EXAMPLE C
Powder containing 1% of active compound Active compound of Example No~ 71.0 9 Zinc oxide 10.0 9 Magnesium oxide 10.0 9 35 Highly disperse silica 2.5 9 Magnesium stearate 1.0 g Talc 75 5 9 1:~556~
- 15 - O.Z. 0050/36919 onO
The active compound is micronized in an air-jet m;ll and then mixed homogeneously with the other compon-ents~ The mixture is forced through a sieve (mesh No. 7) and introduced into polyethylene containers provided with a dusting attachment.
11 Cd C( C'd ) H O
12 ~ 4-Cl-C6H4 13 ~ 2 ~4-C12-C6H3 C2 5 14 N 4_F-C6d4 H O
l S CH 4 F C 6 4 Examples of pharmaceutical formulations:
EXAMP~E A
Tablet containing 250 mg of active compound composition for 1~000 tablets~
Active compound of Example No. 7 250 9 Potato starch 100 9 Lactose 50 9 4X strength gelatine solution 45 9 Talc 10 9 ~2~5~
- 14 - O.Z. 0050!36919 Preparation:
The finely powdered active compound, po~ato starch and lactose are mixed. The mixture is moistened thor-oughly with about 4~ 9 of 4~ strenyth gelatine solution and then converted to fine granules, and these a~e dried.
The dry granules are passed through a sieve and mixed with -10 g of talG and the mixture is converted to tablets on a rotary tablet machine. The tablets are introduced into tightly closing polypropylene containers.
Cream containing 1% of active compound Active compound of Example NoO 71.0 9 Glycerol monostearate 10~0 9 Cetyl alcohol 4~0 g 15 Polyethylene glycol-400 stearate10.0 9 Polyethylene glycol sorbitan monostearate 10.0 9 Propylene glycol 6.0 9 Methyl p-hydroxybenzoate 0.2 g Deminerali~ed water to ma~e up tolOO.û g Pre~ation:
The very finely powdered active compound is sus-pended in propylene glycol, and the suspension is stirred ;nto a melt cons;st;ng of glycerol monostearate, cetyl alcohol, polyethylene glycol-4ûO stearate and polyethy-ZS lene glycol sorb;tan monostearate, the melt being heatedat 65C. An aqueous solution of the methyl p-hydroxy-benzoate, at 70C, ;s emulsif;ed with this mixture.
When it has cooled, the cream is homogenized by means of a colloid mill and is introduced into tubes.
EXAMPLE C
Powder containing 1% of active compound Active compound of Example No~ 71.0 9 Zinc oxide 10.0 9 Magnesium oxide 10.0 9 35 Highly disperse silica 2.5 9 Magnesium stearate 1.0 g Talc 75 5 9 1:~556~
- 15 - O.Z. 0050/36919 onO
The active compound is micronized in an air-jet m;ll and then mixed homogeneously with the other compon-ents~ The mixture is forced through a sieve (mesh No. 7) and introduced into polyethylene containers provided with a dusting attachment.
Claims (7)
1. An azolylmethylcycloacetal of the formula I
(I), where R is phenyl which can be substituted by halogen, or is C1-C6-alkyl, R is hydrogen or C1-C3-alkyl, Z is CH or N, and m is O or 1, and its physiologically tolerated addition salts with acids.
(I), where R is phenyl which can be substituted by halogen, or is C1-C6-alkyl, R is hydrogen or C1-C3-alkyl, Z is CH or N, and m is O or 1, and its physiologically tolerated addition salts with acids.
2. An azolylmethylcycloacetal of the formula I as defined in claim 1, wherein R is tert.-butyl or halogen-substituted phenyl, R1 is hydrogen or methyl, Z
is CH or N, and m is O or 1, and its physiologically tolerated addition salts with acids.
is CH or N, and m is O or 1, and its physiologically tolerated addition salts with acids.
3. 2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl azide and its physiologically tolerated addition salts with acids.
4. 2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dioxolan-5-ylmethyl azide and its physiologi-cally tolerated addition salts with acids.
5. 2-(2,4-Dichlorophenyl)-2-(1H-1,2,4,-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl azide and its physio-logically tolerated addition salts with acids.
6. A therapeutic composition comprising a pharma-ceutical excipient and an effective amount of an azolyl-methylcycloacetal of the formula I as defined in claim 1 or 2 as active compound.
7. A therapeutic composition comprising a pharma-ceutical excipient and an effective amount of an azolyl-methylcycloacetal as defined in claim 3, 4 or 5 as active compound.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843401694 DE3401694A1 (en) | 1984-01-19 | 1984-01-19 | AZOLYLMETHYLCYCLOACETALE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| DEP3401694.5 | 1984-01-19 |
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| Publication Number | Publication Date |
|---|---|
| CA1255682A true CA1255682A (en) | 1989-06-13 |
Family
ID=6225322
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000472307A Expired CA1255682A (en) | 1984-01-19 | 1985-01-17 | Azolylmethylcycloacetals, their preparation and their use as drugs |
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| Country | Link |
|---|---|
| US (1) | US4607045A (en) |
| EP (1) | EP0149814B1 (en) |
| JP (1) | JPS60161984A (en) |
| AT (1) | ATE33837T1 (en) |
| CA (1) | CA1255682A (en) |
| DE (2) | DE3401694A1 (en) |
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| DE3305769A1 (en) * | 1982-06-04 | 1983-12-08 | Bayer Ag, 5090 Leverkusen | PEST CONTROL |
| IT1196528B (en) * | 1986-07-21 | 1988-11-16 | Donegani Guido Ist | AZOLYL DERIVATIVES FOR ANTI-Fungal activity |
| CN105017232B (en) * | 2015-07-29 | 2018-06-08 | 江苏七洲绿色化工股份有限公司 | A kind of synthetic method of triazole bactericidal agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| SU557755A3 (en) * | 1968-08-19 | 1977-05-05 | Янссен Фармасьютика Н.В. (Фирма) | Method for preparing imidazole derivatives |
| US4144346A (en) * | 1977-01-31 | 1979-03-13 | Janssen Pharmaceutica N.V. | Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles |
| US4313953A (en) * | 1978-06-23 | 1982-02-02 | Janssen Pharmaceutica, N.V. | Heterocyclic derivatives of (4-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles |
| AU526321B2 (en) * | 1978-07-24 | 1983-01-06 | Janssen Pharmaceutica N.V. | 1-(2-aryl-4,5-disubstituted-1,3-dioxolan-2-yl-methyl)-1h- imidazoles and 1h-1,2,4-triazoles |
| AU524832B2 (en) * | 1978-07-25 | 1982-10-07 | Janssen Pharmaceutica N.V. | 1-(2-aryl-1,3-dioxan-2-ylmethyl)-1h-imidazoles and 1h-1,2,4 -triazoles |
| US4321272A (en) * | 1980-08-25 | 1982-03-23 | Syntex (U.S.A.) Inc. | Derivatives of substituted N-alkylimidazoles |
| DE3166517D1 (en) * | 1980-11-24 | 1984-11-08 | Janssen Pharmaceutica Nv | NOVEL (2-ARYL-4-PHENYLTHIOALKYL-1,3-DIOXOLAN-2-YL-METHYL) AZOLE DERIVATIVES |
| EP0060962B1 (en) * | 1980-12-10 | 1985-08-07 | Ciba-Geigy Ag | Microbicidal triazolyl methyl dioxolanes and their preparation |
| JPS58134089A (en) * | 1982-02-02 | 1983-08-10 | Yoshiki Hamada | 1,3-dioxolane benzoate derivative and preparation thereof |
| US4375474A (en) * | 1982-02-11 | 1983-03-01 | Syntex (U.S.A.) Inc. | Dioxalane containing imidazole compounds, compositions and use |
| EP0094052A3 (en) * | 1982-05-12 | 1984-07-18 | Hoechst Aktiengesellschaft | 1-(1,3-dioxolan-2-yl-methyl)-1h-imidazoles and -1h-1,2,4-triazoles and their salts, process for their preparation, compositions containing them and their use |
-
1984
- 1984-01-19 DE DE19843401694 patent/DE3401694A1/en not_active Withdrawn
- 1984-12-18 DE DE8484115718T patent/DE3470741D1/en not_active Expired
- 1984-12-18 EP EP84115718A patent/EP0149814B1/en not_active Expired
- 1984-12-18 AT AT84115718T patent/ATE33837T1/en not_active IP Right Cessation
-
1985
- 1985-01-16 US US06/691,851 patent/US4607045A/en not_active Expired - Fee Related
- 1985-01-17 JP JP60005116A patent/JPS60161984A/en active Pending
- 1985-01-17 CA CA000472307A patent/CA1255682A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ATE33837T1 (en) | 1988-05-15 |
| US4607045A (en) | 1986-08-19 |
| DE3401694A1 (en) | 1985-07-25 |
| EP0149814A2 (en) | 1985-07-31 |
| DE3470741D1 (en) | 1988-06-01 |
| EP0149814A3 (en) | 1986-12-10 |
| JPS60161984A (en) | 1985-08-23 |
| EP0149814B1 (en) | 1988-04-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |